Tobacco use is associated with addiction to nicotine, and is the largest cause of preventable mortality in the world. The long-range objectives of these studies are to understand the organization of nAChR complexes at synapses and how nicotine-mediated synaptic activity modulates the process of cholinergic synapse maturation in the CNS. The overall hypothesis of this proposal is that neurexins target neuronal nicotinic acetylcholine receptors (nAChRs) to synapses in the brain and that this process is modulated by nicotine exposure. This hypothesis is based on novel preliminary results showing neurexin-1 (nrx-1) interacts with nAChRs, complimenting recent genome-wide association studies showing the association of single nucleotide polymorphisms (SNPs) in the NRX-1 gene with nicotine dependence. My specific aims are to determine the mechanisms by which nrx-1 targets a4[unreadable]2 nAChRs to synapses and by which the targeting mechanism is modulated by nicotine exposure. To accomplish these goals, nAChRs and neurexins will be studied in neuronal cultures to measure changes in clustering and targeting of nAChRs to synapses. Additionally, changes in neurexin expression will be monitored by quantitative PCR and Western analysis in an animal model of nicotine addiction. The findings from the proposed studies will provide novel information on the mechanisms involved in nicotinic receptor expression and the molecules needed for proper nicotinic receptor function, which may lead to new strategies for tobacco use cessation. In addition, these studies will provide insight into diseases associated with nAChR dysfunction including schizophrenia, sudden infant death syndrome and autism. PUBLIC HEALTH RELEVANCE: Tobacco use is associated with nicotine addiction, and is the largest cause of preventable mortality in the world. Thus, understanding the pathways modulated by nicotine will contribute to treatments for this deadly addiction. Nicotinic receptors have long been associated with drug abuse, therefore examining how nAChRs interact with their binding partners will contribute to our understanding of the cellular and molecular underpinnings of drug dependence. The results from my research also will contribute to our understanding of the effects that drugs of abuse have on the brain during development.